Glutamyl-prolyl-tRNA synthetase (EPRS1) drives tubulointerstitial nephritis-induced fibrosis by enhancing T cell proliferation and activity.

Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1+/+ mice than in the kidneys of TIN-induced Eprs1+/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1+/- mice. TIN-induced fibrosis was also reduced in Rag1-/- mice adoptively transferred with Eprs1+/- T cells compared to the Rag1-/- mice transferred with Eprs1+/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells.

Glomerular crescents are associated with the risk of type 2 diabetic kidney disease progression: a retrospective cohort study.

BACKGROUND: Diabetic kidney disease (DKD) stands as the predominant cause of chronic kidney disease and end-stage kidney disease. Its diverse range of manifestations complicates the treatment approach for patients. Although kidney biopsy is considered the gold standard for diagnosis, it lacks precision in predicting the progression of kidney dysfunction. Herein, we addressed whether the presence of glomerular crescents is linked to the outcomes in patients with biopsy-confirmed type 2 DKD. METHODS: We performed a retrospective evaluation, involving 327 patients diagnosed with biopsy-confirmed DKD in the context of type 2 diabetes, excluding cases with other glomerular diseases, from nine tertiary hospitals. Hazard ratios (HRs) were calculated using a Cox regression model to assess the risk of kidney disease progression, defined as either ≥ 50% decrease in estimated glomerular filtration rates or the development of end-stage kidney disease, based on the presence of glomerular crescents. RESULTS: Out of the 327 patients selected, ten patients had glomerular crescents observed in their biopsied tissues. Over the follow-up period (median of 19 months, with a maximum of 18 years), the crescent group exhibited a higher risk of kidney disease progression than the no crescent group, with an adjusted HR of 2.82 (1.32-6.06) (P = 0.008). The presence of heavy proteinuria was associated with an increased risk of developing glomerular crescents. CONCLUSION: The presence of glomerular crescents is indeed linked to the progression of type 2 DKD. Therefore, it is important to determine whether there is an additional immune-mediated glomerulonephritis requiring immunomodulation, and it may be prudent to monitor the histology and repeat a biopsy.

Hyperlactatemia is a predictor of mortality in patients undergoing continuous renal replacement therapy for acute kidney injury.

BACKGROUND: Hyperlactatemia occurs frequently in critically ill patients, and this pathologic condition leads to worse outcomes in several disease subsets. Herein, we addressed whether hyperlactatemia is associated with the risk of mortality in patients undergoing continuous renal replacement therapy (CRRT) due to acute kidney injury. METHODS: A total of 1,661 patients who underwent CRRT for severe acute kidney injury were retrospectively reviewed between 2010 and 2020. The patients were categorized according to their serum lactate levels, such as high (≥ 7.6 mmol/l), moderate (2.1-7.5 mmol/l) and low (≤ 2 mmol/l), at the time of CRRT initiation. The hazard ratios (HRs) for the risk of in-hospital mortality were calculated with adjustment of multiple variables. The increase in the area under the receiver operating characteristic curve (AUROC) for the mortality risk was evaluated after adding serum lactate levels to the Sequential Organ Failure Assessment (SOFA) and the Acute Physiology and Chronic Health Evaluation (APACHE) II score-based models. RESULTS: A total of 802 (48.3%) and 542 (32.6%) patients had moderate and high lactate levels, respectively. The moderate and high lactate groups had a higher risk of mortality than the low lactate group, with HRs of 1.64 (1.22-2.20) and 4.18 (2.99-5.85), respectively. The lactate-enhanced models had higher AUROCs than the models without lactates (0.764 vs. 0.702 for SOFA score; 0.737 vs. 0.678 for APACHE II score). CONCLUSIONS: Hyperlactatemia is associated with mortality outcomes in patients undergoing CRRT for acute kidney injury. Serum lactate levels may need to be monitored in this patient subset.

Longitudinal trajectory of acidosis and mortality in acute kidney injury requiring continuous renal replacement therapy.

BACKGROUND: Acidosis frequently occurs in severe acute kidney injury (AKI), and continuous renal replacement therapy (CRRT) can control this pathologic condition. Nevertheless, acidosis may be aggravated; thus, monitoring is essential after starting CRRT. Herein, we addressed the longitudinal trajectory of acidosis on CRRT and its relationship with worse outcomes. METHODS: The latent growth mixture model was applied to classify the trajectories of pH during the first 24 hours and those of C-reactive protein (CRP) after 24 hours on CRRT due to AKI (n = 1815). Cox proportional hazard models were used to calculate hazard ratios of all-cause mortality after adjusting multiple variables or matching their propensity scores. RESULTS: The patients could be classified into 5 clusters, including the normally maintained groups (1st cluster, pH = 7.4; and 2nd cluster, pH = 7.3), recovering group (3rd cluster with pH values from 7.2 to 7.3), aggravating group (4th cluster with pH values from 7.3 to 7.2), and ill-being group (5th cluster, pH < 7.2). The pH clusters had different trends of C-reactive protein (CRP) after 24 hours; the 1st and 2nd pH clusters had lower levels, but the 3rd to 5th pH clusters had an increasing trend of CRP. The 1st pH cluster had the best survival rates, and the 3rd to 5th pH clusters had the worst survival rates. This survival difference was significant despite adjusting for other variables or matching propensity scores. CONCLUSIONS: Initial trajectories of acidosis determine subsequent worse outcomes, such as mortality and inflammation, in patients undergoing CRRT due to AKI.

Automated Computational Detection of Interstitial Fibrosis, Tubular Atrophy, and Glomerulosclerosis.

BACKGROUND: Interstitial fibrosis, tubular atrophy (IFTA), and glomerulosclerosis are indicators of irrecoverable kidney injury. Modern machine learning (ML) tools have enabled robust, automated identification of image structures that can be comparable with analysis by human experts. ML algorithms were developed and tested for the ability to replicate the detection and quantification of IFTA and glomerulosclerosis that renal pathologists perform. METHODS: A renal pathologist annotated renal biopsy specimens from 116 whole-slide images (WSIs) for IFTA and glomerulosclerosis. A total of 79 WSIs were used for training different configurations of a convolutional neural network (CNN), and 17 and 20 WSIs were used as internal and external testing cases, respectively. The best model was compared against the input of four renal pathologists on 20 new testing slides. Further, for 87 testing biopsy specimens, IFTA and glomerulosclerosis measurements made by pathologists and the CNN were correlated to patient outcome using classic statistical tools. RESULTS: The best average performance across all image classes came from a DeepLab version 2 network trained at 40× magnification. IFTA and glomerulosclerosis percentages derived from this CNN achieved high levels of agreement with four renal pathologists. The pathologist- and CNN-based analyses of IFTA and glomerulosclerosis showed statistically significant and equivalent correlation with all patient-outcome variables. CONCLUSIONS: ML algorithms can be trained to replicate the IFTA and glomerulosclerosis assessment performed by renal pathologists. This suggests computational methods may be able to provide a standardized approach to evaluate the extent of chronic kidney injury in situations in which renal-pathologist time is restricted or unavailable.

Can sodium fluorescein cause contrast-induced nephropathy?

BACKGROUND: Contrast-induced nephropathy (CIN) is a common cause of acute kidney injury (AKI), and can be diagnosed when the etiology of AKI is unclear other than via a contrast agent. Fluorescent angiography (FAG) with fluorescein sodium dye is generally considered to be safe for patients with kidney diseases. However, it remains unresolved whether or not FAG can induce CIN. METHODS: Patients from two tertiary hospitals who underwent FAG and had serum creatinine results within 4 weeks before FAG and 3 days after FAG between 2001 and 2017 were retrieved. Cases with concurrent iodinated contrast imaging or undergoing dialysis were excluded from the analysis. CIN was defined by two criteria: CIN criteria as >0.5 mg/dL or >25% increase in serum creatinine (sCr) level within 3 days after FAG, and contrast-induced acute kidney injury (CIAKI) criteria as ≥0.3 mg/dL increase within 2 days or ≥50% increase within 7 days after FAG. RESULTS: A total of 979 patients were screened, and we found 124 patients with AKI after FAG. After excluding 32 patients with clear causes of AKI other than FAG, the incidence rates of CIN were 7.3% by CIN criteria and 6.4% by CIAKI criteria. CIN incidence had a U-shaped distribution according to chronic kidney disease (CKD) stages in CIN criteria, while linear association between CIN incidence and CKD stages were found in CIAKI criteria. Kaplan-Meier curves showed the CIN group was significantly associated with end-stage renal disease (ESRD) progression (log-rank P < 0.001, in both CIN criteria and CIAKI criteria), and adjusted hazard ratios by multivariable Cox regression were 2.23 [95% confidence interval (CI) 1.468-3.378] in CIN criteria and 2.17 (95% CI 1.462-3.232) in CIAKI criteria. CONCLUSIONS: According to CIN and CIAKI criteria, FAG may cause CIN and appeared to be a possible risk factor for ESRD progression. However, CIN or CIAKI criteria themselves may overestimate AKI and require meticulous attention to the interpretation of results.

Hyperchloremia is associated with poor renal outcome after coronary artery bypass grafting.

BACKGROUND: Hyperchloremia is associated with the risks of several morbidities and mortality. However, its relationship with acute kidney injury (AKI) and end-stage renal disease (ESRD) in patients undergoing coronary artery bypass grafting (CABG) remains unresolved. METHODS: A total of 2977 patients undergoing CABG between 2003 and 2015 were retrospectively reviewed from two tertiary hospitals. Patients were categorized by serum chloride levels into normochloremia (95-105 mmol/L), mild hyperchloremia (106-110 mmol/L), and severe hyperchloremia (> 110 mmol/L). The odds ratios (ORs) for AKI and hazard ratios (HRs) for ESRD were calculated after adjustment for multiple covariates. The death-adjusted risk of ESRD was additionally evaluated. RESULTS: Postoperative AKI occurred in 798 patients (26.5%). The hyperchloremia group had a higher risk of AKI than the normochloremia group, wherein the risk was incremental depending on the severity of hyperchloremia, as follows: ORs were 1.26 (1.06-1.51) and 1.95 (1.52-2.51) in the mild and severe hyperchloremia groups, respectively. During a median period of 7 years (maximum 15 years), 70 patients (2.3%) had ESRD. The severe hyperchloremia group was at an elevated risk of ESRD compared with the normochloremia group, with an HR of 2.43 (1.28-4.63). Even after adjusting for the competing risk of death, hyperchloremia was associated with the risk of ESRD. CONCLUSIONS: Preoperative hyperchloremia is associated with poor renal outcomes such as AKI and ESRD after CABG. Accordingly, serum chloride should be monitored in patients undergoing CABG.

Target value of mean arterial pressure in patients undergoing continuous renal replacement therapy due to acute kidney injury.

BACKGROUND: Although patients undergoing continuous renal replacement therapy (CRRT) due to acute kidney injury (AKI) frequently have instability in mean arterial pressure (MAP), no consensus exists on the target value of MAP related to high mortality after CRRT. METHODS: A total of 2,292 patients who underwent CRRT due to AKI in three referral hospitals were retrospectively reviewed. The MAPs were divided into tertiles, and the 3rd tertile group served as a reference in the analyses. The major outcome was all-cause mortality during the intensive care unit period. The odds ratio (OR) of mortality was calculated using logistic regression after adjustment for multiple covariates. The nonlinear relationship regression model was applied to determine the threshold value of MAP related to increasing mortality. RESULTS: The mean value of MAP was 80.7 ± 17.3 mmHg at the time of CRRT initiation. The median intensive care unit stay was 5 days (interquartile range, 2-12 days), and during this time, 1,227 (55.5%) patients died. The 1st tertile group of MAP showed an elevated risk of mortality compared with the 3rd tertile group (adjusted OR, 1.28 [1.03-1.60]; P = 0.029). In the nonlinear regression analysis, the threshold value of MAP was calculated as 82.7 mmHg. Patients with MAP < 82.7 mmHg had a higher mortality rate than those with ≥ 82.7 mmHg (adjusted OR, 1.21 [1.01-1.45]; P = 0.037). CONCLUSIONS: Low MAP at CRRT initiation is associated with a high risk of mortality, particularly when it is < 82.7 mmHg. This value may be used for risk classification and as a potential therapeutic target.

MEST-C pathological score and long-term outcomes of child and adult patients with Henoch-Schönlein purpura nephritis.

BACKGROUND: Henoch-Schönlein purpura nephritis (HSPN), a small-vessel vasculitis, shares renal pathological features with immunoglobulin A nephropathy. Oxford classification of immunoglobulin A nephropathy pathology has been updated to the MEST-C score, but its application in HSPN remains unresolved. METHODS: Two hundred and thirteen patients with biopsy-proven HSPN were retrieved from the Seoul National University Hospital between 2000 and 2017. Renal outcome risks (i.e., end-stage renal disease or doubling of serum creatinine) were evaluated according to MEST-C scores after stratification by age: 113 children aged < 18 years (9.2 ± 3.6 years) and 100 adults aged ≥18 years (38.6 ± 18.3 years). We pooled our data with four previous cohort studies in which MEST or MEST-C scores were described in detail. RESULTS: Twenty-one child (19%) and 16 adult (16%) patients reached the renal outcome during the median follow-up periods of 12 years and 13 years, respectively (maximum 19 years). In children, M1 and T1/T2 scores revealed worse renal outcomes than did M0 and T0 scores, respectively, whereas the T score was the only factor related to worse outcomes in adult patients after adjusting for multiple clinical and laboratory variables. The pooled data showed that M1, S1, and T1/T2 in children and E1 and T1/T2 in adults were correlated with poorer renal outcomes than those of their counterpart scores. CONCLUSIONS: The Oxford classification MEST-C scores can predict long-term renal outcomes in patients with HSPN.

Effect of steroids and relevant cytokine analysis in acute tubulointerstitial nephritis.

BACKGROUND: Acute tubulointerstitial nephritis (ATIN) is an important cause of acute kidney injury and often a potentially reversible disease. However, the role of steroids in ATIN remains controversial and the underlying mechanisms remain unresolved. METHODS: A total of 113 adult patients with biopsy-proven ATIN were recruited from three tertiary referral centers. Of 102 patients with idiopathic or drug-induced ATIN, outcomes such as renal recovery, end-stage renal disease, and all-cause mortality were compared between the steroid-treated and non-treated groups. Plasma and urine inflammatory cytokine levels at the time of biopsy were analyzed in patients (n = 33) using a bead-based multiplex assay and compared with those of healthy individuals (n = 40). RESULTS: Steroids were used in 92 (81.4%) of the total patients and in 82 (80.3%) patients with idiopathic or drug-induced ATIN. The rate of renal recovery and the risks of end-stage renal disease and mortality were not different between the steroid-treated and non-treated groups. Despite using a propensity score matching method (n = 20 in each group), none of the outcomes were different between the two groups. Several cytokines, such as monocyte chemotactic protein-1, interferon-α, and interleukin-6 and interleukin-8 levels, were markedly elevated in plasma and urine of patients compared with those in healthy individuals. However, cytokines related to Th2 response, such as IL-10, IL-33, were not different between the two groups. CONCLUSIONS: Steroid use does not affect the overall outcome of ATIN. Based on the fact that targeting therapy should be investigated to improve outcomes, the present cytokine results will be helpful for developing a novel therapy for ATIN.

Mortality associated with the neutrophil-lymphocyte ratio in septic acute kidney injury requiring continuous renal replacement therapy.

BACKGROUND: Sepsis is an important cause of acute kidney injury in intensive care unit patients, accounting for 15% to 20% of renal replacement therapy prescriptions. The neutrophil-lymphocyte ratio (NLR), a marker of systemic inflammation and immune response, was previously associated with the mortality rate in multiple conditions. Herein, we aimed to examine how the NLR relates to the mortality rate in septic acute kidney injury patients requiring continuous renal replacement therapy (CRRT). METHODS: The NLRs of 6 and 18 were used for dividing NLRs into three groups and, thus, were set higher than those in previous studies accounting for steroid use in sepsis. Cox proportional hazard models were used to calculate hazard ratios of mortality outcomes before and after matching their propensity scores. RESULTS: A total of 798 septic acute kidney injury patients requiring CRRT were classified into three NLR groups (low, <6 [n = 277]; medium, ≥6 and <18 [n = 115], and high, ≥18 [n = 406], respectively). The in-hospital mortality rates per group were 83.4%, 74.8%, and 70.4%, respectively (p < 0.001). Per the univariable Cox survival analysis after propensity score matching, a high NLR was related to approximately 24% reduced mortality. The survival benefit of the high NLR group compared with the other two groups remained consistent across all subgroups, showing any p for interactions of >0.05. CONCLUSION: A high NLR is associated with better clinical outcomes, such as low mortality, in septic acute kidney injury patients undergoing CRRT.

Intradialytic hypotension and worse outcomes in patients with acute kidney injury requiring intermittent hemodialysis.

Background: Intradialytic hypotension (IDH) is a critical complication related to worse outcomes in patients undergoing maintenance hemodialysis. Herein, we addressed the impact of IDH on mortality and other outcomes in patients with severe acute kidney injury (AKI) requiring intermittent hemodialysis. Methods: We retrospectively reviewed 1,009 patients who underwent intermittent hemodialysis due to severe AKI. IDH was defined as either dialysis discontinuation due to hemodynamic instability or a decrease in systolic blood pressure (BP) of ≥30 mmHg, with or without a nadir systolic BP of <90 mmHg during the first session. The primary outcome was all-cause mortality, and transfer to the intensive care unit (ICU) due to unstable status was additionally analyzed. Hazard ratios (HRs) of outcomes were calculated using a Cox regression model after adjusting for multiple variables. Risk factors for IDH were evaluated using a logistic regression model. Results: IDH occurred in 449 patients (44.5%) during the first hemodialysis session. Patients with IDH had a higher mortality rate than those without IDH (40% vs. 23%; HR, 1.30; 95% confidence interval [CI], 1.02-1.65). The rate of ICU transfer was higher in patients experiencing IDH than in those without IDH (17% vs. 11%; HR, 1.43; 95% CI, 1.02-2.02). Factors such as old age, high BP and pulse rate, active malignancy, cirrhosis, and hypoalbuminemia were associated with an increased risk of IDH episodes. Conclusion: The occurrence of IDH is associated with worse outcomes in patients with AKI requiring intermittent hemodialysis. Therefore, careful monitoring and early intervention of IDH may be necessary in this patient subset.

Spatially Aware Transformer Networks for Contextual Prediction of Diabetic Nephropathy Progression from Whole Slide Images.

Diabetic nephropathy (DN) in the context of type 2 diabetes is the leading cause of end-stage renal disease (ESRD) in the United States. DN is graded based on glomerular morphology and has a spatially heterogeneous presentation in kidney biopsies that complicates pathologists' predictions of disease progression. Artificial intelligence and deep learning methods for pathology have shown promise for quantitative pathological evaluation and clinical trajectory estimation; but, they often fail to capture large-scale spatial anatomy and relationships found in whole slide images (WSIs). In this study, we present a transformer-based, multi-stage ESRD prediction framework built upon nonlinear dimensionality reduction, relative Euclidean pixel distance embeddings between every pair of observable glomeruli, and a corresponding spatial self-attention mechanism for a robust contextual representation. We developed a deep transformer network for encoding WSI and predicting future ESRD using a dataset of 56 kidney biopsy WSIs from DN patients at Seoul National University Hospital. Using a leave-one-out cross-validation scheme, our modified transformer framework outperformed RNNs, XGBoost, and logistic regression baseline models, and resulted in an area under the receiver operating characteristic curve (AUC) of 0.97 (95% CI: 0.90-1.00) for predicting two-year ESRD, compared with an AUC of 0.86 (95% CI: 0.66-0.99) without our relative distance embedding, and an AUC of 0.76 (95% CI: 0.59-0.92) without a denoising autoencoder module. While the variability and generalizability induced by smaller sample sizes are challenging, our distance-based embedding approach and overfitting mitigation techniques yielded results that suggest opportunities for future spatially aware WSI research using limited pathology datasets.

Spatially Aware Transformer Networks for Contextual Prediction of Diabetic Nephropathy Progression from Whole Slide Images.

Diabetic nephropathy (DN) in the context of type 2 diabetes is the leading cause of end-stage renal disease (ESRD) in the United States. DN is graded based on glomerular morphology and has a spatially heterogeneous presentation in kidney biopsies that complicates pathologists' predictions of disease progression. Artificial intelligence and deep learning methods for pathology have shown promise for quantitative pathological evaluation and clinical trajectory estimation; but, they often fail to capture large-scale spatial anatomy and relationships found in whole slide images (WSIs). In this study, we present a transformer-based, multi-stage ESRD prediction framework built upon nonlinear dimensionality reduction, relative Euclidean pixel distance embeddings between every pair of observable glomeruli, and a corresponding spatial self-attention mechanism for a robust contextual representation. We developed a deep transformer network for encoding WSI and predicting future ESRD using a dataset of 56 kidney biopsy WSIs from DN patients at Seoul National University Hospital. Using a leave-one-out cross-validation scheme, our modified transformer framework outperformed RNNs, XGBoost, and logistic regression baseline models, and resulted in an area under the receiver operating characteristic curve (AUC) of 0.97 (95% CI: 0.90-1.00) for predicting two-year ESRD, compared with an AUC of 0.86 (95% CI: 0.66-0.99) without our relative distance embedding, and an AUC of 0.76 (95% CI: 0.59-0.92) without a denoising autoencoder module. While the variability and generalizability induced by smaller sample sizes are challenging, our distance-based embedding approach and overfitting mitigation techniques yielded results that sugest opportunities for future spatially aware WSI research using limited pathology datasets.

Consulting to nephrologist when starting continuous renal replacement therapy for acute kidney injury is associated with a survival benefit.

BACKGROUND: Several studies suggest improved outcomes for patients with kidney disease who consult a nephrologist. However, it remains undetermined whether a consultation with a nephrologist is related to a survival benefit after starting continuous renal replacement therapy (CRRT) due to acute kidney injury (AKI). METHODS: Data from 2,397 patients who started CRRT due to severe AKI at Seoul National University Hospital, Korea between 2010 and 2020 were retrospectively collected. The patients were divided into two groups according to whether they underwent a nephrology consultation regarding the initiation and maintenance of CRRT. The Cox proportional hazards model was used to calculate the hazard ratio (HR) of mortality during admission to the intensive care unit after adjusting for multiple variables. RESULTS: A total of 2,153 patients (89.8%) were referred to nephrologists when starting CRRT. The patients who underwent a nephrology consultation had a lower mortality rate than those who did not have a consultation (HR = 0.47 [0.40-0.56]; P < 0.001). Subsequently, patients who had nephrology consultations were divided into two groups (i.e., early and late) according to the timing of the consultation. Both patients with early and late consultation had lower mortality rates than patients without consultations, with HRs of 0.45 (0.37-0.54) and 0.51 (0.42-0.61), respectively. CONCLUSIONS: Consultation with a nephrologist may contribute to a survival benefit after starting CRRT for AKI.

Impact of intradialytic hypotension on mortality following the transition from continuous renal replacement therapy to intermittent hemodialysis.

BACKGROUND: The transition of dialysis modalities from continuous renal replacement therapy (CRRT) to intermittent hemodialysis (iHD) is frequently conducted during the recovery phase of critically ill patients with acute kidney injury. Herein, we addressed the occurrence of intradialytic hypotension (IDH) after this transition, and its association with the mortality risk. METHODS: A total of 541 patients with acute kidney injury who attempted to transition from CRRT to iHD at Seoul National University Hospital, Korea from 2010 to 2020 were retrospectively collected. IDH was defined as a discontinuation of dialysis because of hemodynamic instability plus a nadir systolic blood pressure <90 mm Hg or a decrease in systolic blood pressure ≥30 mm Hg during the first session of iHD. Odds ratios (ORs) of outcomes, such as in-hospital mortality and weaning from RRT, were measured using a logistic regression model after adjusting for multiple variables. RESULTS: IDH occurred in 197 patients (36%), and their mortality rate (44%) was higher than that of those without IDH (19%; OR, 2.64; 95% confidence interval [CI], 1.70-4.08). For patients exhibiting IDH, the iHD sessions delayed successful weaning from RRT (OR, 0.62; 95% CI, 0.43-0.90) compared with sessions on those without IDH. Factors such as low blood pressure, high pulse rate, low urine output, use of mechanical ventilations and vasopressors, and hypoalbuminemia were associated with IDH risk. CONCLUSIONS: IDH occurrence following the transition from CRRT to iHD is associated with high mortality and delayed weaning from RRT.

Discovery of Novel Digital Biomarkers for Type 2 Diabetic Nephropathy Classification via Integration of Urinary Proteomics and Pathology.

Background: The heterogeneous phenotype of diabetic nephropathy (DN) from type 2 diabetes complicates appropriate treatment approaches and outcome prediction. Kidney histology helps diagnose DN and predict its outcomes, and an artificial intelligence (AI)-based approach will maximize clinical utility of histopathological evaluation. Herein, we addressed whether AI-based integration of urine proteomics and image features improves DN classification and its outcome prediction, altogether augmenting and advancing pathology practice. Methods: We studied whole slide images (WSIs) of periodic acid-Schiff-stained kidney biopsies from 56 DN patients with associated urinary proteomics data. We identified urinary proteins differentially expressed in patients who developed end-stage kidney disease (ESKD) within two years of biopsy. Extending our previously published human-AI-loop pipeline, six renal sub-compartments were computationally segmented from each WSI. Hand-engineered image features for glomeruli and tubules, and urinary protein measurements, were used as inputs to deep-learning frameworks to predict ESKD outcome. Differential expression was correlated with digital image features using the Spearman rank sum coefficient. Results: A total of 45 urinary proteins were differentially detected in progressors, which was most predictive of ESKD (AUC=0.95), while tubular and glomerular features were less predictive (AUC=0.71 and AUC=0.63, respectively). Accordingly, a correlation map between canonical cell-type proteins, such as epidermal growth factor and secreted phosphoprotein 1, and AI-based image features was obtained, which supports previous pathobiological results. Conclusions: Computational method-based integration of urinary and image biomarkers may improve the pathophysiological understanding of DN progression as well as carry clinical implications in histopathological evaluation.

Risk of ventricular tachycardia and its outcomes in patients undergoing continuous renal replacement therapy due to acute kidney injury.

BACKGROUND: Despite efforts to treat critically ill patients who require continuous renal replacement therapy (CRRT) due to acute kidney injury (AKI), their mortality risk remains high. This condition may be attributable to complications of CRRT, such as arrhythmias. Here, we addressed the occurrence of ventricular tachycardia (VT) during CRRT and its relationship with patient outcomes. METHODS: This study retrospectively enrolled 2,397 patients who started CRRT due to AKI from 2010 to 2020 at Seoul National University Hospital in Korea. The occurrence of VT was evaluated from the initiation of CRRT until weaning from CRRT. The odds ratios (ORs) of mortality outcomes were measured using logistic regression models after adjustment for multiple variables. RESULTS: VT occurred in 150 patients (6.3%) after starting CRRT. Among them, 95 cases were defined as sustained VT (i.e., lasting ≥30 seconds), and the other 55 cases were defined as non-sustained VT (i.e., lasting <30 seconds). The occurrence of sustained VT was associated with a higher mortality rate than a nonoccurrence (OR, 2.04 and 95% confidence interval [CI], 1.23-3.39 for the 30- day mortality; OR, 4.06 and 95% CI, 2.04-8.08 for the 90-day mortality). The mortality risk did not differ between patients with non-sustained VT and nonoccurrence. A history of myocardial infarction, vasopressor use, and certain trends of blood laboratory findings (such as acidosis and hyperkalemia) were associated with the subsequent risk of sustained VT. CONCLUSION: Sustained VT occurrence after starting CRRT is associated with increased patient mortality. The monitoring of electrolytes and acid-base status during CRRT is essential because of its relationship with the risk of VT.

Automatic segmentation of atrial fibrillation and flutter in single-lead electrocardiograms by self-supervised learning and Transformer architecture.

OBJECTIVES: Automatic detection of atrial fibrillation and flutter (AF/AFL) is a significant concern in preventing stroke and mitigating hemodynamic instability. Herein, we developed a Transformer-based deep learning model for AF/AFL segmentation in single-lead electrocardiograms (ECGs) by self-supervised learning with masked signal modeling (MSM). MATERIALS AND METHODS: We retrieved data from 11 open-source databases on PhysioNet; 7 of these databases included labeled ECGs, while the other 4 were without labels. Each database contained ECG recordings with durations of ≥30 s. A total of 24 intradialytic ECGs with paroxysmal AF/AFL during 4 h of hemodialysis sessions at Seoul National University Hospital were used for external validation. The model was pretrained by predicting masked areas of ECG signals and fine-tuned by predicting AF/AFL areas. Cross-database validation was used for evaluation, and the intersection over union (IOU) was used as a main performance metric in external database validation. RESULTS: In the 7 labeled databases, the areas marked as AF/AFL constituted 41.1% of the total ECG signals, ranging from 0.19% to 51.31%. In the evaluation per ECG segment, the model achieved IOU values of 0.9254 and 0.9477 for AF/AFL segmentation and other segmentation tasks, respectively. When applied to intradialytic ECGs with paroxysmal AF/AFL, the IOUs for the segmentation of AF/AFL and non-AF/AFL were 0.9896 and 0.9650, respectively. Model performance by different training procedure indicated that pretraining with MSM and the application of an appropriate masking ratio both contributed to the model performance. It also showed higher IOUs of AF/AFL labels than in previous studies when training and test databases were matched. CONCLUSION: The present model with self-supervised learning by MSM performs robustly in segmenting AF/AFL.

Real-time dual prediction of intradialytic hypotension and hypertension using an explainable deep learning model.

Both intradialytic hypotension (IDH) and hypertension (IDHTN) are associated with poor outcomes in hemodialysis patients, but a model predicting dual outcomes in real-time has never been developed. Herein, we developed an explainable deep learning model with a sequence-to-sequence-based attention network to predict both of these events simultaneously. We retrieved 302,774 hemodialysis sessions from the electronic health records of 11,110 patients, and these sessions were split into training (70%), validation (10%), and test (20%) datasets through patient randomization. The outcomes were defined when nadir systolic blood pressure (BP) < 90 mmHg (termed IDH-1), a decrease in systolic BP ≥ 20 mmHg and/or a decrease in mean arterial pressure ≥ 10 mmHg (termed IDH-2), or an increase in systolic BP ≥ 10 mmHg (i.e., IDHTN) occurred within 1 h. We developed a temporal fusion transformer (TFT)-based model and compared its performance in the test dataset, including receiver operating characteristic curve (AUROC) and area under the precision-recall curves (AUPRC), with those of other machine learning models, such as recurrent neural network, light gradient boosting machine, random forest, and logistic regression. Among all models, the TFT-based model achieved the highest AUROCs of 0.953 (0.952-0.954), 0.892 (0.891-0.893), and 0.889 (0.888-0.890) in predicting IDH-1, IDH-2, and IDHTN, respectively. The AUPRCs in the TFT-based model for these outcomes were higher than the other models. The factors that contributed the most to the prediction were age and previous session, which were time-invariant variables, as well as systolic BP and elapsed time, which were time-varying variables. The present TFT-based model predicts both IDH and IDHTN in real time and offers explainable variable importance.